Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • C07K14/575—Hormones
  • C07K14/655—Somatostatins
  • C07K14/6555—Somatostatins at least 1 amino acid in D-form
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P39/00—General protective or antinoxious agents
  • A61P39/02—Antidotes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides

Definitions

• This invention relates to therapeutic peptides.
• the invention features in one aspect thereof an octapeptide of the formula: wherein each A1 and A2, independently, is H, C1 ⁇ 12 alkyl, C7 ⁇ 10 phenylalkyl, R1CO (where R1 is C1 ⁇ 20 alkyl, C3 ⁇ 20 alkenyl, C3 ⁇ 20 alkynyl, phenyl, naphthyl, or C7 ⁇ 10 phenylalkyl), or R2OCO (where R2 is C1 ⁇ 10 alkyl or C7 ⁇ 10 phenylalkyl), provided that when one of A1 or A2 is R1CO or R2OCO, the other must be H;
• A3 is CH2-A6 (where A6 is pentafluorophenyl, naphthyl, pyridyl, phenyl, or o-, m-, or, more preferably, p-substituted phenyl, where the substituent is a halogen, NH2, NO2,
• the configuration of the molecule at the carbon atom to which A3 is bonded is not given, to indicate that the amino acid residue of which A3 is a substituent can have the D- or L- configuration.
• 3 0r 5 positions is meant carbon atoms in the ortho position relative to the -OH group of tyrosine.
• Preferred compounds of this formula include D- ⁇ -Nal-Cys-Tyr(I)-D-Trp-Lys-Val-Cys-Thr-NH2 (also termed [I]-BIM-23014C); D-Phe-Cys-Tyr(I)-D-Trp-Lys- ⁇ -­Aminobutyric acid-Cys-Thr-NH2; pentafluoro-D-Phe-Cys-­Tyr(I)-D-Trp-Lys-Val-Cys-Thr-NH2; N-Ac-D- ⁇ -Nal-Cys-­Tyr(I)-D-Trp- Lys-Val-Cys-Thr-NH2; D- ⁇ -Nal-Cys-Tyr(I)-­D-Trp-Lys-Val-Cys- ⁇ -Nal-NH2; D-Phe-Cys-Tyr-(I)
• the invention features an octapeptide having a biological activity of somatostatin, having at amino acid position 3 a tyrosine residue, the tyrosine having an iodine atom at its 3 or 5 carbon position, or a parmaceutically acceptable salt of said octapeptide.
• biological activity of somatostatin is meant a polypeptide exhibiting GH-­releasing-inhibiting activity.
• a therapeutically effective amount of the compound is admixed with a pharmaceutically acceptable carrier substance (e.g. magnesium carbonate, lactose, or a phospholipid with which the therapeutic compound can form a micelle).
• a pharmaceutically acceptable carrier substance e.g. magnesium carbonate, lactose, or a phospholipid with which the therapeutic compound can form a micelle.
• the most preferred carrier substance is mannitol.
• Such compositions include a pill, tablet, capsule, or liquid for oral administration to a human patient, a spreadable cream, gel, lotion, or ointment for application to the skin of a human patient in need of the compound, a liquid capable of being administered nasally as drops or spray, or a liquid capable of intravenous, parenteral, subcutaneous, or intraperitoneal administration.
• the pill, tablet or capsule can be coated with a substance capable of protecting the composition from the gastric acid in the patient's stomach for a period of time sufficient to allow the composition to pass undisintegrated into the patient's small intestine.
• the therapeutic composition can also be administered in the form of an oil emulsion or dispersion in conjunction with a lipophillic salt such as a pamoic acid.
• the therapeutic composition can also be in the form of a biodegradable sustained release formulation for intramuscular administration. For maximum efficacy, zero order release is desired. Zero order release can be obtained using an implantable or external pump, e.g., Infusaid TM pump, to administer the therapeutic composition.
• our compounds may be seen as polypeptides having somatostatin-like activity.
• D- ⁇ -naphthylalanine at position 1, and Tyr at position 3, modified to have an iodine atom at carbon position 3 or 5, and Val at position 6, are modifications which particularly enhance activity and stability.
• the compounds can be provided in the form of pharmaceutically acceptable salts or complexes.
• preferred salts or complexes are those with therapeutically acceptable organic acids, e.g., acetic, lactic, maleic, citric, malic, ascorbic, succinic, benzoic, salicylic, methanesulfonic, toluenesulfonic, or pamoic acid, as well as polymeric acids such as tannic acid or carboxymethyl cellulose, and salts with inorganic acids such as the hydrohalic acids, e.g., hydrochloric acid, sulfuric acid, or phosphoric acid.
• hydrohalic acids e.g., hydrochloric acid, sulfuric acid, or phosphoric acid.
• octapeptides examples include but not limited to, octapeptides, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids, amino acids
• the first step in the preparation of D- ⁇ -naphthylalanine-Cys-Tyr(I)-D-Trp-Lys-Val-Cys-Thr-­NH2 was the preparation of the intermediate tert-butyloxycarbonyl-D- ⁇ -napthylalanine-S-­methylbenzyl-Cys-Tyr-D-Trp-N ⁇ -benzyloxycarbonyl-­Lys-Val-S-methylbenzyl-Cys-O-benzyl-Thr-­benzyhydrylamine resin, as follows.
• Benzhydrylamine-polystyrene resin (Vega Biochemicals, Inc.) in the chloride ion form was placed in the reaction vessel of a Beckman 990B peptide synthesizer programmed to perform the following reaction cycle: (a) methylene chloride; (b) 33% trifluoroacetic acid in methylene chloride (2 times for 1 and 25 min each); (c) methylene chloride; (d) ethanol; (e) methylene chloride; (f) 10% triethylamine in chloroform.
• the neutralized resin was stirred with Boc-O-benzyl-threonine and diisopropylcarbodiimide (1.5 mmole each) in methylene chloride for 1 h and the resulting amino acid resin was then cycled through steps (a) to (g) in the above wash program.
• the following amino acids (1.5 mmole) were then coupled successively by the same procedure: Boc-S-methylbenzyl-Cys, Boc-Val, Boc-Ne-benzyloxycarbonyl-lysine, Boc-D-Trp, Boc-Tyr, Boc-S-methylbenzyl-Cys, Boc-D- ⁇ -naphthylalanine.
• the resin was washed and dried and then mixed with anisole (4 ml) and anhydrous hydrogen fluoride (36 ml) at 0°C and stirred for 45 min. (one can also use thioanisole, trifluoroacetic acid, and trifluoromethane sulfonic acid at a ratio of 1:90:9, for 6h). Excess hydrogen fluoride was evaporated rapidly under a stream of dry nitrogen and free peptide precipitated and washed with ether. The crude peptide was then dissolved in 800 ml of 90% acetic acid to which was added I2 in methanol until a permanent brown color was present. The solution was then stirred for 1 h before removing the solvent in vacuo .
• the column was eluted with a linear gradient of 10-50% acetonitrile in 0.1% trifluoroacetic acid in water. Fractions were examined by thin layer chromatography and analytical high performance liquid chromatography and pooled to give maximum purity and if desired, a different salt prepared, e.g., acetate or phosphate. Repeated lyophilization of the solution from water gave 170 mg of the product as a white, fluffy powder.
• a different salt prepared, e.g., acetate or phosphate.
• the product was found to be homogeneous by Hplc and Tlc. Amino acid analysis of an acid hydrolysate confirmed the composition of the octapeptide. The octapeptide was then iodinated as follows.
• iodination may be by use of: a) Chloramine-T/NaI; b) Lactoperoxidase-glucose oxidase (LP-GO)/NaI; c) Lactoperoxidase-H2O2 (LP-H2O2)/NaI; d) Enzymobeads (immobilized LP-GO)/NaI (purchased from Bio-Rad Laboratories); e) Iodobeads (immobilized chloromine-T)NaI (purchased from Pierce Chemical Company); f) Iodogen/NaI; g) Iodine/KI; and h) Iodine monochloride.
• the iodinated products are purified, e.g., by HPLC to separate di-iodination products of tyrosine, and unreacted starting material, from the desired iodinated octapeptide.
• HPLC HPLC to separate di-iodination products of tyrosine, and unreacted starting material, from the desired iodinated octapeptide.
• the following is a specific example showing Chloramine-T/NaI iodination of the octapeptide BIM-23014C.
• the solution ( ⁇ 250ml) was injected into a preparative HPLC column and eluted with a gradient as follows.
• the HPLC instrument was a SepTech 800ST; and the column was a Vydac 15-20 ⁇ C18 column.
• the mobile phase consisted of A (0.05M NH2OAc, ph 4.5); and B (0.05M NH4OAc, pH 4.5, and CH3CN, at a ratio of 1:1) with the gradient constructed from 30%B to 75%B over 45 minutes, and then 75%B for 10 minutes, at a flow rate of about 30ml/min. Progress was followed using a ⁇ of 228nm. Six fractions were collected, and some assayed for octapeptide content by HPLC. Those with the majority of the desired octapeptide were combined and evaporated to a lower volume ( ⁇ 80ml) by rotary evaporation under high vacuum.
• the resulting liquid was reloaded onto the preparative HPLC column for a final purification using conditions as before.
• Six fractions were collected and assayed for content by HPLC.
• One fraction contained the octapeptide and was concentrated to about 100ml by rotary evaporation, transferred to a 500ml Buchner flask, frozen, and lyophilized for 24 hours.
• the sample was redissolved in 50ml of H2O and relyophilized for 48 hours.
• the final product (190mg), a fluffy white powder, was transferred to a labelled sample storage bottle, capped and stored at -20°C.
• the product is [I]-BIM-23014C.
• Octapeptides having the formulae:pentafluoro-D-Phe-Cys-Tyr(I)-D-Trp-Lys-Val-­ Cys-Thr-NH2, D-Phe-Cys-Tyr(I)-D-Trp-Lys- ⁇ -­aminobutyric acid-Cys-Thr-NH2, N-Ac-D- ⁇ -Nal-Cys-Tyr(I)­-D-Trp- Lys-Val-Cys-Thr-NH2, D- ⁇ --Nal-Cys-Tyr(I)-D-­Trp- Lys-Val-Cys- ⁇ -Nal-NH2, D-Phe-Cys-Tyr(I)-D-Trp-Lys-­Val-Cys- ⁇ -Nal-NH2; D- ⁇ -Nal-Cys-Tyr(I)-D-Trp-Lys-­Val
• the compounds When administered to mammals, particularly humans, (e.g. orally, topically, intravenously, parenterally in a sustained release, biodegradable form, nasally, or by suppository), the compounds can be effective to inhibit GH release and to a lesser extent insulin, glucagon, and pancreatic exocrine secretion, and to therapeutically affect the central nervous sytem.
• the compounds can be administered to a mammal, e.g. a human, in the dosages used for somatostatin or, because of their greater potency, in smaller dosages.
• Our compounds can be used for the treatment of cancer, particularly growth hormone-dependent cancer (e.g., bone, cartilage, pancreas (endocrine and exocrine), prostate, or breast), acromegaly and related hypersecretroy endocrine states, or of bleeding ulcers in emergency patients and in those suffering from pancreatitis or diarrhea.
• the compounds can also be used in the management of diabetes and to protect the liver of patients suffering from cirrhosis or hepatitis.
• the compounds can also be used to treat Alzheimer's disease, as analgesics to treat pain by acting specifically on certain opiate receptors, and as gastric cytoprotective compounds for ulcer therapy.
• the compounds can also be used to treat certain types of mushroom poisoning.
• the compounds can also be used to treat diabetes-related retinopathy.
• the anti-cancer activity of the compounds may be related to their ability to antagonize cancer-related growth factors such as epidermal growth factor.
• the compounds can act as an antiproliferative agents by preventing the release of, or antagonizing the effects of, auto/paramine growth factor.
• the compounds can be administered to a mammal, e.g., a human, in a dosage of 0.01 to 50 mg/kg/day, preferably 0.1 to 5 mg/kg/day.

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• 1990
  • 1990-03-14 CA CA002012115A patent/CA2012115C/fr not_active Expired - Fee Related
  • 1990-03-15 EP EP90302760A patent/EP0389180B1/fr not_active Expired - Lifetime
  • 1990-03-15 DE DE69015671T patent/DE69015671T2/de not_active Expired - Fee Related
  • 1990-03-15 ES ES90302760T patent/ES2068333T3/es not_active Expired - Lifetime
  • 1990-03-15 AT AT90302760T patent/ATE116659T1/de not_active IP Right Cessation
  • 1990-03-15 JP JP2065511A patent/JP2888912B2/ja not_active Expired - Fee Related
  • 1990-03-15 DK DK90302760.5T patent/DK0389180T3/da active

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